PROJECT SUMMARY Children with ADHD are at risk for a host of deleterious outcomes including impaired social relations, academic difficulties, criminality, and comorbid psychopathology (substance use, depression, anxiety). Many of these difficulties emerge and exacerbate during adolescence; therefore, it is crucial to understand the developmental trajectory of ADHD-associated changes in brain and behavior during this sensitive period. Further, there is increasing recognition that sex may be an important moderator of the clinical manifestations of ADHD, with adolescent boys showing more impulsive risk-taking while girls show more emotional dysregulation. To date, few studies of ADHD have taken a longitudinal approach to examining sex-based differences in behavioral changes and brain development into adolescence. For our currently funded grant, ?Neural Basis of Response Control in ADHD,? we have thus far assessed a large cohort of school-age, pre-pubescent children with ADHD, in which we oversampled for girls. Our findings have revealed sexually dimorphic patterns of ADHD-associated impairments in response control and related structural brain abnormalities. Specifically, boys, but not girls, with ADHD show impaired basic motor response control and abnormalities in premotor structure; in contrast, girls with ADHD show impaired cognitive response control (e.g., when working memory is necessary to guide response selection/inhibition) and a predominance of abnormalities in prefrontal structure. Furthermore, we find that girls, but not boys, with ADHD show abnormalities in limbic structure and fail to show improvements in response control with reward. Given the known sexual dimorphisms in brain development, our findings in pre- pubescent children with ADHD raise important questions: Will these sex differences in abnormal patterns of brain structure and response control persist into adolescence and are they predictive of functional outcomes (e.g., academic, executive function, affective)? Therefore, building upon our results and successful recruitment, the goal of this renewal, is to examine ?Adolescent Changes in Brain and Behavior in Boys and Girls with ADHD.? Using a longitudinal mixed model design, we will delineate and contrast developmental changes in response control and brain structure in ADHD girls and boys with that of typically-developing children, and examine the impact on adolescent mental health and behavioral outcomes. This approach is highly consistent with the strategic research objectives of the National Institute of Mental Health (NIMH) including ?Defining the developmental trajectories of mental disorders? and ?Developing new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures? (Strategic Aims 2.1 and 1.4). Furthermore, in line with the Research Domain Criteria (RDoC) approach we are proposing to examine the dimensional construct of response control in children with ADHD from multiple levels of analysis including neural structure and connectivity, behavioral expression, and relation to functional outcomes, with the ultimate goal of identifying bio-behavioral markers of impairment and adjustment in children with ADHD.